HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus. Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002). Other relevant patent disclosures describing the synthesis of HCV protease inhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); U.S. Pat. No. 5,861,297 (1999); U.S. Patent Publications 20050153877, 20050261200 and 20050065073.
Many HCV protease inhibitors comprise macrocyclic rings, the syntheses of which can pose special problems. Specifically, such synthesis use a ring closing metathesis (RCM) reaction, which is known to be inefficient. For example, in order to limit by-product/impurity formation, such as dimerization/oligomerization of starting alkenes, the RCM is frequently run at a high dilution (>100 volumes, 100 L/Kg) or with slow addition rates to limit the concentration of starting material. However, even with the slow addition of reactants, the RCM fails to provide reactions without significant contaminants. Furthermore, high dilution reactions are typically not practical on a large scale, thereby inhibiting the efficient and successful commercialization of such products.
WO 2007/030656 (2007) (hereinafter “WO '656”) describes a protection/deprotection strategy that adds two steps to the overall chemical transformation but allows for dramatic reductions in the overall volume of the reaction (10-20 times) with relatively minor impact on the yield of reaction. WO '656 principally uses Boc (tert-butyl carboxy) protecting groups. Moreover, WO '656 describes the use of a limited number of protecting group on HCV protease inhibitor compound. Other related publications include Nicola, T. et al. First Scale-Up to Production Scale of a Ring Closing Metathesis Reaction Forming a 15-Membered Macrocycle as a Precursor of an Active Pharmaceutical Ingredient. Organic Process Research & Development, 9, 513-515 (2005) and Yee, N. K. et al. Efficient Large-Scale Synthesis of BILN 2061, a Potent HCV Protease Inhibitor, by a Convergent Approach Based on Ring-Closing Metathesis. J. Org. Chem. 71, 7133-7145 (2006).